Retinoids are vitamin A derivatives which have preventative and therapeutic value in the treatment of some cancers. The mechanism of action of retinoids is thought to be mediated, at least in part, by interaction with nuclear receptors resulting in modulation of gene transcription. Recent studies suggest that retinoids enhance cellular reactive oxygen species (ROS) formation, particularly superoxide anion. Superoxide and its dismutation product, hydrogen peroxide, are signaling molecules; therefore, alteration of redox status by retinoids may contribute to modulation of differentiation genes. Manganese superoxide dismutase (MnSOD) is an essential, mitochondrial localized primary antioxidant which has been shown to enhance cellular differentiation. The overall goal of this project is to investigate the link between MnSOD and all trans retinoic acid (ATRA) in a model of neuroblastoma differentiation. The hypothesis to be tested is that upregulation of MnSOD is an essential, initial transcriptional event in ATRA differentiation of neuroblastoma which subsequently enhances mitochondrial function, resulting in chemoresistance. Using an ATRA responsive neuroblastoma cell line, SK-N-SH, the hypothesis will be tested in four specific aims. Specific aim 1 will determine if NFkappaB activation is responsible for MnSOD induction in response to ATRA. Specific aim 2 will determine if ROS, generated as a result of ATRA administration, contribute to upregulation of MnSOD. Specific aim 3 will determine if MnSOD is essential to ATRA dependent differentiation in the SK-N-SH cell line. Specific aim 4 will determine if MnSOD protects cells from cisplatin-induced apoptosis as a result of ATRA administration. The basis of this project is to delineate the link between ATRA mediated differentiation of neuroblastoma and MnSOD upregulation. This proposal will generate data which will determine MnSOD's role as essential to the differentiation process and/or protective against chemotherapeutic agents which initiate mitochondrial mediated programmed cell death.